This proposal, entitled "PTSD and drug dependence: neuroimaging of reward circuitry" is a response to NIDA Request for R01 Applications (#DA-04-001; Stress and Drug Abuse: Epidemiology, Etiology, Prevention and Treatment). The primary goal of this proposal is to investigate brain reward function as a potential neuropathological basis for substance use disorders (SUDs) comorbidity in posttraumatic stress disorder (PTSD). Basic neuroscience and clinical findings suggest that brain reward circuitry is altered by chronic stress exposure in ways that may be important for facilitating SUDs. We hypothesize that: 1) functionally impaired brain reward mechanisms may comprise a neural substrate underlying core PTSD symptoms of reduced reactivity to natural rewarding stimuli or emotional numbing and that 2) this neural substrate is further altered by the presence of comorbid SUDs. The proposed project is designed to test these hypotheses integrating functional magnetic resonance imaging, psychopharmacology and cognitive psychology to empirically measure reward responses in PTSD, cocaine dependence, PTSD with comorbid cocaine dependence and in health. The proposed experiments have already been successfully performed in separate cohorts of healthy volunteers and piloted in PTSD subjects with and without cocaine dependence. The published data and preliminary results suggest unique patterns of hemodynamic responses in the nucleus accumbens (NAc) and related structures during reward processing along with PTSD-related abnormalities in performance on a behavioral probe of reward function. Three distinct experimental paradigms to be used in this project include a) low doses of an FDA-approved euphorigenic drug, morphine, which can be safely administered to drug-naive subjects, b) social reward in the form of visual processing of attractive faces and c) monetary incentive stimuli incorporated into a gambling task. We expect to find that in PTSD patients the magnitude of the NAc's activation in response to the three rewarding stimuli will be smaller relative to healthy controls, but larger than in individuals with comorbid PTSD and cocaine dependence. This research plan will provide important leads for understanding and preventing the development of SUDs in the context of chronic stress exposure or PTSD. Furthermore our project may offer insights on the pathogenesis of emotional numbing symptoms, which cause severe disability not only in PTSD patients, but also in those suffering from other neuropsychiatric conditions such as SUDs, schizophrenia and major depression.